Separation of optical antipodes with urea



United States atent SEPARATION OF OPTICAL ANTIPODES WITH UREA WilhelmSchlenk, Mannheim-Feudenheim, Germany, assignor to Badische Anilin- &Soda-Fabrik Aktiengesellschaft, Ludwigshafen am Rhine, Germany NoDrawing. Application'Angust 11, 1954 Serial No. 449,255

Claims priority, application Germany May 8, 1952 7 Claims. (Cl. 260-865)This invention relates. to a new and improved method of separatingoptical antipodes.

The separation ofracemic mixtures into their two different opticallyactive components offers considerable difficulties in chemical practice.Mechanical sorting of the enantiomorphic crystal individuals beingimpracticable in commercial scale processes, it has been necessary tofind out suitable optically active substances for each particular casewhich react with the antipodes to form compounds, as for example salts,amides, esters, or complex compounds, which unlike the antipodesthemselves, do not behave as image and mirror-image and as a result areseparable from each other by reason of their different physicalproperties. The auxiliary substances chiefly used in this separationtechnique are alkaloids or other optically active natural substances,which for their high cost are a major disadvantage in commercialoperation.

I have now found that optical antipodes can be separated by bringingtogether the racemic mixture with substances which form therewithinclusion compounds, the inclusion lattice belonging to one of the 15symmetry classes (C1: C5, C2: CZV: D2, S4 C4 D26. D4 C3: D3: C D T and0) without a center of symmetry. By inclusion lattice I mean the crystallattice existing in the presence of the compounds to be included, whichlattice often shows a spiral asymmetrical arrangement of the molecules.These lattices form inclusion compounds which preferentially containmolecules of the d-form or the l-form. By splitting up these inclusioncompounds, the respective dextroor laevo-rotatory ant-ipodes can berecovered.

A substance which is especially suitable for the production of suchinclusion compounds is urea. It is known that urea forms additioncompounds with certain substances (Liebigs Annalen der Chemie, 565, 204(1949)) and that mixtures of substances may thus be split up. Theinclusion compounds according to the present invention are formed in acorresponding Way. The urea is added to the mixture to be separated inthe solid form or dissolved, for example, in methyl alcohol. Thecrystals which separate are split up into their components in knownmanner, as for example by treatment with methyl alcohol or water.

Whether in any given case it is mainly inclusion compounds whichseparate as crystals containing the dextrorotatory or the laevo-rotatoryform of the antipodes depends on the first formation of nuclei. Byinoculation of the saturated solution with crystals of a urea adduct ofan optically active compound, it is possible to accelerate the formationof crystals which contain predominantly the dextroor the laevo-rotatoryinclusion component. It is good practice to provide for thecrystallization proceeding slowly.

By adding further amounts of the substance forming the inclusioncompounds, as for example urea, to the mother liquor, fresh inclusioncompounds can be sep- ICE arated which may be united with the firstprecipitate for working up. The oppositely rotatory antipode' graduallybecomes enriched in the mother liquor and" can be separated therefrom inthe form of aninclusion compound, preferably after inoculation with acorresponding ystal. m

The following examples will further illustrate invention but theinvention is not restricted to these examples. The parts are parts byweight.

Example 1 20 parts of a racemic mixture of Z-chloroctane-(rotation O)are mixed with parts of asaturated methyl alcoholic solution of urea.The precipitate which forms immediately is dissolved by gentle heating.The solution is then allowed to cool slowly to +7 C. Aninclusioncompound of urea and 2 -chloroctane (8.5 parts) separates out from whichthe 2-chloroctane can be separated by treatment with water. It shows aspecific rotation of a =-l-(l.30. By appropriate inoculation furtheramounts of the dextro-rotatory antipode can be separated as an inclusioncompound.

Example 2 15 parts of a racemic mixture of theheptyl ester ofozchlorobutyric acid are dissolved in 100 parts of methanol and, afterheating the solution to a temperature of 21 C., urea is added until thesolution is just saturated with urea at the said temperature. Any smallexcess of urea is filtered off. The mixture is further heated to about24 C. and then cooled down to 7 C. over a period of 20 hours whilestirring slowly, 0.01 part of the ".(-).-2- chloroctane adduct obtainedaccording to Example. 1 being added as an inoculating agent at 22, 21,20 and 19 C. After the lapse of 20 hours. the crystal pulp precipitated(about 5 parts) is filtered 0E and dissociated by means of water. Thereare obtained about 1125 parts of the heptyl ester of a-chlorobutyricacid which has a specific rotation of a =+1.52.

Example 3 20 parts of the racemic diamyl ester of malic acid aredissolved in 100 parts of methanol and the solution is saturated withurea at a temperatureof 22 C. as described in Example 2. The mixtureis'"further heated to about 25 C. and then cooled down to 6 C. over aperiod of 24 hours while stirring, 0.01 part of a urea adduct containingdextro-rotatory (oz =+1.23) citronellyl caprinate being added as aninoculating agent at 23, 22, 21, and 20 C. 0n dissociation of the adductobtained there are obtained 6.2 parts of the diamyl ester of malic acidwhich has a specific rotation of :4222

As shown in the above examples, only about 8 to 31% of the racemicmixture is initially precipitated as urea inclusion compounds whichcontain predominantly one of the optical antipodes. The precipitate isthen separated from the portion of the racemic mixture which 3r'emainsin solution, thereby efiecting a partial separation of theoptical antipodes.

Examples of further substances which can be separated into their,optically active components by the method according tom invention arez'2' -ch1orocta1ie, '2-clilorononane, ,Z-chlorddecane, 2-chlorotridecane, ,3 chlorononane, 3-chlorododecane,

",Decanol-3,,dodecanol-3, a

' The octyle's'ter of a chlorop'ropionic acid, the octyl ester of,m-bromopropionic acid, a.

' The hexylfester, of lactic acid, the heptyl ester of lactic "acid, thedecyl ester of lactic acid, f v

The heptyl ester of 'lz-chlorobutyric acid, the decyl ester ofa-bromobutyricacid, the heptyl ester of lit-chlorobutyric acid, theoctyl ester of u-methylbutyric acid, the octyl' ester of'a-hydroxybutyricacid, the heptyl ester offl-hydrox'y butyric acid, the octylester of it-aminobutyric acid, V

' ,The' heptyl ester of oi chlorovaleric acid, the heptyl ester ofy-chlorovaleric -acid,'the octyl ester of ,B-methylvale'ric acid,theheptyl ester of hydroxyvaleric acid,

The decyl ester of a-bromocaproic acid, the heptyl ester of7-chlorocaproic acid, the octyl ester of 6-chloro caproic acid, thedecyl esterof a/y-dimethyl valeric acid, The octyl ester of leucine, thedecyl ester of leucine, the decyl ester of a-chloroisocaproic acid, thedecyl ester oft-methyl caproic acid,

The butanoI-Z-ester ofrcaprylic acid, the butanol-Z- ester of caprinicacid," the octanol-2-ester of caprylic acid, the Octanol-Z-esterofcaprinic acid,

The diamyl ester of a-chlorosuccinic acid, the diamyl ester of malicac'id, the diheptyl ester of a-methyl-succinic acid, thediheptylesterof, dichlorosucci'nic acid,

The diamyl ester of a-chloroglutaric acid, the diheptyl esterfofu-methylglutaric acid, the dibutyl ester of achloroadipic acid. l r

application is a continuation-in-part of my application Serial No.352,587 filed May I,- 1953, now abandoned.

What I claim is:

,1. A process for the separation of optical antipodes in a-racemicmixture which comprises: preparing a solution containing both urea and aracemic mixture, said racemic-mixture 'being capable of forming ureainclusion compounds with urea by precipitation from said solution;slowly. reducing the temperature of said solution and initiallyprecipitatingv only about 8 to 31% of said racemic mixture as ureainclusion compounds, said precipitated urea inclusion compoundscontaining predominantly one offsaid optical antipodes; and separatingsaid initially precipitated urea "inclusion compounds containingpredominantly one of said optical antipodesfrom the portion of saidracemic mixture remaining in solution which containspre'dominantly theother of said optical antipodes. a Y .Y r

2. A process as claimed in claim 1' for the separation of the opticalantipodes inracemic 2-chloroctane.

3 A process for the separation of optical antipodes in a racemic-mixturewhich comprises: preparing a .solution containing both urea and aracemic mixture, said racemic mixture being -capable of forming ureainclusion compounds with urea by precipitation from said solution;slowly reducing the temperature of said solution and initiallyprecipitating only about 8 to 31% of said racemic mixture as ureainclusion compounds, said precipitated urea inclusionjcompoundscontaining predominantly one of said optical antipodes; separating saidinitially precipitated urea inclusion'compoundscontaining predominantlyone of said optical antipodes from the portion of saidfracemic mixtureremaining 'in-solution which contains predominantly the otherof-saidoptical antipodes; and separating said precipitated urea inclusioncompounds into their components of urea and predominantly said one ofthe said optical antipodes.

4. A process as claimed in claim 3 for the separation of the opticalantipodes in racemicheptyl ester' of mchlorobutyric acid. Q

5. A process as claimed in claim 3 for the separation of the opticalantipodes inracemic 'diamyl ester of malic acid. s I

6. A process as claimed in claim 3, wherein the optical antipodes in aracemic mixture of-an alkyl ester of an aliphatic carboxylic acid areseparated. 7

7. A process for the separation ofoptical antipodes in a racemic mixturewhichicomprises: preparing a so lution containing both urea and aracemic mixture, said racemic mixture being capable of forming urea'inclusion compounds with urea by precipitation from said solution;

' slowly reducing the temperature of'saidfsolution and tating ureainclusion compounds containing initially precipitating only about 8 to31%"of said'racemic mixture as urea inclusion compounds, saidprecipitated urea inclusion compounds containing predominant 1y one ofsaid optical antipodes; separating said initially precipitated ureainclusion compounds containing predominantlyone of said opticalantipodes from the portion of said racemic mixture remaining in solutionwhich contains predominantly'the, other of'said optical antipodes;separating said precipitated urea inclusion com pounds into theircomponents 'of urea and-predominantly said one of the said opticalantipodes; and recovering said other of said.optical-;antipodes from theportion of said racemic mixture remaining'in solution by addingadditional amounts of urea to said solution andprecipily said other ofsaid optical antipodes. I

References Cited in the fileofthis patent UNITED STATES PA ENTS 1 rBowman et al A r: 29;'19s2 2,632,002 Gross Mar. -17, 1953 2,634,261Fetterly Apr; 7, 1953 2,658,887 Arnold et al. 'Nov. 10, 1953 2,662,879Foster Dec. 15,; 1953 2,681,333 Gorin June 15, 1954 2,702,289 Bowman etal. Feb.'15, 1955 7 OTHER REFERENCES g t English et al.:' Principles ofOrganic Chemistry, McGraw-Hill, New York, 1949, page4l0.. T Merck Index(6tl1ied.), Merck & Co., Rahway, New Jersey, 1952, page 691. a

predominant-

1. A PROCESS FOR THE SEPARATION OF OPTICAL ANTIPODES IN A RACEMICMIXTURE WHICH COMPRISES: PREPARING A SOLUTION CONTAINING BOTH UREA AND ARACEMIC MIXTURE, SAID RACEMIC MIXTURE BEING CAPABLE OF FORMING UREAINCLUSION COMPOUNDS WITH UREA BY PRECIPITATION FROM SAID SOLUTION;SLOWLY REDUCING THE TEMPERATURE OF SAID SOLUTION AND INITIALLYPRECIPITATING ONLY ABOUT 8 TO 31% OF SAID RACEMIC MIXTURE AS UREAINCLUSION COMPOUNDS, SAID PRECIPITATED UREA INCLUSION COMPOUNDSCONTAINING PREDOMINANTLY ONE OF SAID OPTICAL ANTIPODES; AND SEPARATINGSAID INITIALLY PRECIPITATED UREA INCLUSION COMPOUNDS CONTAININGPREDOMINANTLY ONE OF SAID OPTICAL ANTIPODES FROM THE PORTION OF SAIDRACEMIC MIXTURE REMAINING IN SOLUTION WHICH CONTAINS PREDOMINANTLY THEOTHER OF SAID OPTICAL ANTIPODES.